Triple combination therapy for treating Crohn&#39;s disease

ABSTRACT

The invention features new a method for treating inflammatory bowel disease, including Crohn&#39;s Disease (CD) or ulcerative colitis in a human patient, comprising administering to a patient a combination therapy comprising an anti-α4β7 antibody, a TNFα antagonist, and an immunomodulator.

RELATED APPLICATIONS

This application is a United States National Phase under 35 U.S.C. § 371of International Application No. PCT/US2017/031089, filed on May 4,2017, which claims

the benefit of U.S. Provisional Application No. 62/331,813 filed on May4, 2016. The entire contents of the foregoing applications are herebyincorporated by reference.

BACKGROUND

Inflammatory bowel disease (IBD) is a chronic, relapsing, inflammatorydisorder of the gastrointestinal (GI) tract that includes 2 entities,namely ulcerative colitis (UC) and Crohn's disease (CD). In contrast tothe diffuse, superficial, continuous inflammation limited to the colonin UC, the inflammation of CD is focal, may be transmural, and caninvolve any segment of the GI tract from mouth to anus. The prevalenceof CD is approximately 150/100,000 of the United States (US) population.The characteristic pathology involves a chronic inflammatory infiltrateconsisting of neutrophils and macrophages. Hallmarks of CD includegranulomatous inflammation and aphthous ulceration. CD is neithermedically or surgically curable at the current time.

Untreated CD patients commonly develop structural complications thatinclude stricture and fistula formation, which commonly result inhospitalizations and surgery over time. When examining 306 CD patientsfrom the US, Thia et al. (2010, Gastroenterology 139:1147-55) showedthat the cumulative risk of developing CD complications of eitherstricturing or penetrating disease was 33.7% at 5 years and 50.8% at 20years after establishment of CD diagnosis. The natural course of thedisease can range from an indolent course with prolonged periods ofremission to aggressive, incapacitating disease associated withstructural bowel wall damage. Certain patients have aggressive CD, whichcould be defined as having a high relapse rate, development ofpenetrating disease, need for repeat surgery, or multiple admissions forflares. The pathophysiology of IBD is complex as multiple environmentalfactors interact with the genotype of an individual to cause expressionof disease. Published risk factors for aggressive disease includeinvolvement of the upper GI tract and ileum, penetrating disease, earlyage at diagnosis, smoking, extensive ulceration of the mucosa, hightiters of certain serum antibodies, and mutations of thenucleotide-binding oligomerization domain-containing protein 2 (NOD2)gene. The ability to more readily predict which patients will be athigher risk for complications and target more intensive, early treatmentto that group would be invaluable. The Crohn's Disease Personalized Riskand Outcome Prediction Tool (PROSPECT), which incorporates clinical,serological, and genetic variables, has been developed by Siegel et al.(Aliment. Pharmacol. Ther. 2016, 43:262-71; Inflamm. Bowel Dis. 2011,17:30-38). This tool is used to predict the probability of developingcomplications related to CD, specifically strictures or internalpenetrating disease. The output of the predictive model allows riskstratification of patients from low to medium to high risk ofcomplications within a 3-year period.

Treatment with TNF-antagonist therapy substantially improved the care ofpatients with CD refractory to corticosteroids, immunomodulators, andmesalamine. In 2010, the SONIC trial demonstrated that combinationtherapy with the TNF antagonist infliximab and immunomodulatorazathioprine further significantly improved treatment efficacy. About40% of patients, however, will not achieve remission after initiation ofa combined TNF antagonist and immunomodulator. Thus, there remains anurgent unmet medical need for a combination therapy that can improveremission rates and modify disease progression, particularly forpatients who are at higher risk for CD complications.

SUMMARY OF THE INVENTION

The invention relates to methods of treating patient having inflammatorybowel disease (e.g., Crohn's disease (CD) or ulcerative colitis (UC))using combination therapies that can improve remission rates and modifydisease progression.

In one aspect, the patient is at moderate to high risk of complicationfrom the inflammatory bowel disease. In an embodiment, the patient is ahigh risk CD patient.

In one aspect, the invention provides a method of treating a patienthaving Crohn's disease using a triple combination therapy comprising ahumanized anti-α4β7 antibody, adalimumab, and an immunomodulator, andthe triple combination therapy is administered to the patient accordingto the following dosing regimen: an initial dose of 300 mg of humanizedanti-α4β7 antibody as an intravenous infusion, followed by a secondsubsequent dose of 300 mg of humanized anti-α4β7 antibody as anintravenous infusion at about two weeks after the initial dose; followedby a third subsequent dose of 300 mg of the humanized anti-α4β7 antibodyas an intravenous infusion at about six weeks after the initial dose; aninitial dose of 160 mg of adalimumab as a subcutaneous injection,followed by a second subsequent dose of 80 mg of adalimumab as asubcutaneous injection, followed by a third subsequent dose of 40 mg ofadalimumab at about four weeks after the initial dose; and an initialdose of 15 mg of immunomodulator orally; wherein the dosing regimenresults in endoscopic remission and further wherein the anti-α4β7antibody comprises an antigen binding region of nonhuman origin and atleast a portion of an antibody of human origin, the humanized antibodyhas binding specificity for the α4β7 complex, and the antigen-bindingregion comprises the CDRs:

-   -   Light chain: CDR1 SEQ ID NO:7        -   CDR2 SEQ ID NO:8 and        -   CDR3 SEQ ID NO:9; and    -   Heavy chain: CDR1 SEQ ID NO:4        -   CDR2 SEQ ID NO:5 and        -   CDR3 SEQ ID NO:6.

In one embodiment, the humanized anti-α4β7 antibody is administered tothe patient over about 30 minutes.

In one embodiment, the humanized anti-α4β7 antibody has a heavy chainvariable region sequence of amino acids 20 to 140 of SEQ ID NO:1. In oneembodiment, the humanized anti-α4β7 antibody has a light chain variableregion sequence of amino acids 20 to 131 of SEQ ID NO:2. In yet anotherembodiment, the humanized anti-α4β7 antibody has a heavy chaincomprising amino acids 20 to 470 of SEQ ID NO:1 and a light chaincomprising amino acids 20 to 238 of SEQ ID NO:2. In one embodiment, thehumanized anti-α4β7 antibody is vedolizumab.

In one embodiment, the immunomodulator is methotrexate.

In one aspect, the method further comprises administering a subsequentdose of 300 mg of the humanized anti-α4β7 antibody as an intravenousinfusion at about eight weeks after the third subsequent dose.

In one aspect, the method further comprises administering a subsequentdose of 108 mg of the humanized anti-α4β7 antibody as subcutaneousinjection at about every two, three or four weeks after the thirdsubsequent dose.

In one aspect, concomitant corticosteroid use by the patient is taperedto discontinuation during the triple combination therapy.

In one aspect, the invention provides a method of treating a patienthaving an inflammatory bowel disease, comprising administering to thepatient vedolizumab, adalimumab, and methotrexate according to a triplecombination therapy wherein the triple combination therapy comprisesadministering vedolizumab at a dose of 300 mg at weeks 0, 2, and 6,followed by administration every 8 weeks thereafter; subcutaneouslyadministering a 160 mg dose of adalimumab at week 0, an 80 mg dose ofadalimumab at week 2, and a 40 mg dose of adalimumab at week 4 and everytwo weeks thereafter; and administering methotrexate. In one embodiment,adalimumab is discontinued at week 26. In one embodiment, methotrexateis administered orally. In one embodiment, methotrexate is administeredat a dose of 15 mg. In one embodiment, methotrexate is discontinued atweek 34. In one embodiment, the inflammatory bowel disease is Crohn'sdisease. In one embodiment, the inflammatory bowel disease is moderatelyto severely active Crohn's disease. In one embodiment, the patient is ahigh risk CD patient. In one embodiment, the patient is selected as ahigh risk CD patient prior to administration of the triple combinationtherapy. In one embodiment, the inflammatory bowel disease is ulcerativecolitis. In one embodiment the ulcerative colitis is moderately toseverely active ulcerative colitis.

In one aspect, the invention provides a method of treating a patienthaving an inflammatory bowel disease, comprising administering to thepatient vedolizumab, infliximab, and methotrexate according to a triplecombination therapy. The triple combination therapy can compriseadministering vedolizumab at a dose of 300 mg at weeks 0, 2, and 6,followed by administration every 8 weeks thereafter; intravenouslyadministering infliximab at a dose of 5 mg/kg at weeks 0, 2 and 6, andthen every eight weeks thereafter; and administering methotrexate. Inone embodiment, methotrexate is administered orally. In one embodiment,methotrexate is administered at a dose of 15 mg. In one embodiment,methotrexate is discontinued at week 34. In one embodiment, theinflammatory bowel disease is Crohn's disease. In one embodiment, theinflammatory bowel disease is moderately to severely active Crohn'sdisease. In one embodiment, the patient is a high risk CD patient. Inone embodiment, the patient is selected as a high risk CD patient priorto administration of the triple combination therapy. In one embodiment,the inflammatory bowel disease is ulcerative colitis. In one embodiment,the ulcerative colitis is moderately to severely active ulcerativecolitis.

In one aspect, the invention provides a method of treating a patienthaving an inflammatory bowel disease, comprising administering to thepatient vedolizumab, golimumab, and methotrexate according to a triplecombination therapy. The triple combination therapy can compriseadministering vedolizumab at a dose of 300 mg at weeks 0, 2, and 6,followed by administration every 8 weeks thereafter; subcutaneouslyadministering golimumab at a dose of 200 mg at week 0, 100 mg at week 2,and 100 mg every four weeks thereafter; and administering methotrexate.In one embodiment, methotrexate is administered orally. In oneembodiment, methotrexate is administered at a dose of 15 mg. In oneembodiment, methotrexate is discontinued at week 34. In one embodiment,the inflammatory bowel disease is Crohn's disease. In one embodiment,the inflammatory bowel disease is moderately to severely active Crohn'sdisease. In one embodiment, the patient is a high risk CD patient. Inone embodiment, the patient is selected as a high risk CD patient priorto administration of the triple combination therapy. In one embodiment,the inflammatory bowel disease is ulcerative colitis. In one embodiment,the ulcerative colitis is moderately to severely active ulcerativecolitis.

In one aspect, the invention provides a method of treating a patienthaving an inflammatory bowel disease, comprising administering to thepatient vedolizumab, certolizumab pegol, and methotrexate according to atriple combination therapy. The triple combination therapy can compriseadministering vedolizumab at a dose of 300 mg at weeks 0, 2, and 6,followed by administration every 8 weeks thereafter; subcutaneouslyadministering certolizumab at a dose of 400 mg at week 0, 400 mg atweeks 2 and 4, and optionally 400 mg every four weeks thereafter; andadministering methotrexate. In one embodiment, methotrexate isadministered orally. In one embodiment, methotrexate is administered ata dose of 15 mg. In one embodiment, methotrexate is discontinued at week34. In one embodiment, the inflammatory bowel disease is Crohn'sdisease. In one embodiment, the inflammatory bowel disease is moderatelyto severely active Crohn's disease. In one embodiment, the patient is ahigh risk CD patient. In one embodiment, the patient is selected as ahigh risk CD patient prior to administration of the triple combinationtherapy. In one embodiment, the inflammatory bowel disease is ulcerativecolitis. In one embodiment, the ulcerative colitis is moderately toseverely active ulcerative colitis.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic illustrating an overview of the study design.

DETAILED DESCRIPTION

The present invention relates to a method of treating inflammatory boweldisease (e.g., Crohn's Disease or ulcerative colitis) with a triplecombination therapy. The method comprises administering a triplecombination therapy, comprising an anti-integrin α4β7 (e.g.,vedolizumab), a TNFα antagonist (e.g., adalimumab), and animmunomodulator (e.g., methotrexate), to a patient with Crohn's Disease,particularly a patient at high risk for developing complications.

In one aspect, the patient is administered the triple combinationtherapy through one or more administration routes. In some embodiments,the anti-integrin is administered as an infusion, the TNF antagonist asa subcutaneous injection, and the immunomodulator orally.

In some embodiments, the anti-integrin component of the triplecombination therapy is an antibody, such as an anti-α4β7 antibody. Insome embodiments, the anti-α4β7 antibody is a humanized antibody, e.g.,a humanized antibody with the epitopic specificity of Act-1 mousemonoclonal antibody. In some embodiments, the anti-α4β7 antibody isvedolizumab.

In some embodiments, the TNF antagonist is adalimumab. In someembodiments, the TNF antagonist is infliximab, golimumab, orcertolizumab pegol.

In some embodiments, the immunomodulator is methotrexate. In someembodiments, the immunomodulator is azathioprine or 6-mercaptopurine.

Definitions

The term “combination therapy”, as used herein, refers to theadministration of two or more therapeutic substances, e.g., an anti-α4β7antibody and another drug. The other drug(s) may be administeredconcomitant with, prior to, or following the administration of ananti-α4β7 antibody. The term “triple combination therapy” as usedherein, refers to the administration of at least three therapeuticsubstances, e.g., an anti-α4β7 antibody, an anti-TNF antibody, andmethotrexate.

The terms “TNFα antagonist” or “TNF antagonist”, as used interchangeablyherein, refer to a therapeutic agent that inhibits, antagonizes, and/orneutralizes TNFα activity. Examples of a TNF antagonist include, but arenot limited to, adalimumab, infliximab, golimumab, certolizumab pegol,and etanercept.

The term “high risk Crohn's Disease (CD) patient” refers to a patienthaving Crohn's Disease who has at least a 20% chance of a diseasecomplication by year 2 following diagnosis as determined by the Crohn'sDisease Personalized Risk and Outcome Prediction Tool (PROSPECT)predictive tool (Siegel, et al., Aliment. Pharmacol. Ther. 2016;43:262-271). In one embodiment, the methods disclosed herein are used totreat a patient in this particular subpopulation.

Alternatively, the term “high risk Crohn's Disease (CD) patient” refersto a patient having Crohn's Disease who has a risk of complications asdefined by the 2014 American Gastroenterological Association (AGA) CDClinical Care Pathway Criteria (Sandborn, Gastroenterology 2014,147:702-705). The criteria assess the severity of the current and priordisease burden, such as initial diagnosis <30 years of age, extensiveanatomic involvement, perianal and/or severe rectal disease, deepulcers, prior surgical resection or stricturing and/or penetratingbehavior. In one embodiment, the methods disclosed herein are used totreat a patient whose CD has at least one of these criteria. In oneembodiment, the methods disclosed herein are not used to treat a patientwho has had prior surgical resection.

“Baseline” as used herein describes a value of a parameter which ismeasured prior to the initial dose of a treatment. It can refer to ameasurement of a sample obtained the same day, the day before, duringthe week before initial treatment, i.e., at a time period before thefirst dose when little change is expected until after the first dose andvalues of the measurement obtained after the first dose can be comparedto this baseline value to represent the change caused by the dose.

The term “pharmaceutical formulation” refers to a preparation thatcontains an α4β7 antagonist, such as an anti-α4β7 antibody, in such formas to permit the biological activity of the antibody to be effective,and which contains no additional components which are unacceptably toxicto a subject to which the formulation would be administered.

The cell surface molecule, “α4β7 integrin,” or “α4β7,” is a heterodimerof an α₄ chain (CD49D, ITGA4) and a β₇ chain (ITGB7). Each chain canform a heterodimer with an alternative integrin chain, to form α₄β₁ orα_(E)β₇. Human α₄ and β₇ genes (GenBank (National Center forBiotechnology Information, Bethesda, Md.) RefSeq Accession numbersNM_000885 and NM_000889, respectively) are expressed by B and Tlymphocytes, particularly memory CD4+ lymphocytes. Typical of manyintegrins, α4β7 can exist in either a resting or activated state.Ligands for α4β7 include vascular cell adhesion molecule (VCAM),fibronectin and mucosal addressin (MAdCAM (e.g., MAdCAM-1)).

An “α4β7 antagonist” is a molecule which antagonizes, reduces orinhibits the function of α4β7 integrin. Such antagonist may antagonizethe interaction of α4β7 integrin with one or more of its ligands. Anα4β7 antagonist may bind either chain of the heterodimer or a complexrequiring both chains of the α4β7 integrin, or it may bind a ligand,such as MAdCAM. An α4β7 antagonist may be an antibody which performssuch binding function, such as an anti-α4β7-integrin antibody or“anti-α4β7 antibody”. In some embodiments, an α4β7 antagonist, such asan anti-α4β7 antibody, has “binding specificity for the α4β7 complex”and binds to α4β7, but not to α4β1 or αEβ7.

The term “antibody” or “antibodies” herein is used in the broadest senseand specifically covers full length antibody, antibody peptide(s) orimmunoglobulin(s), monoclonal antibodies, chimeric antibodies (includingprimatized antibodies), polyclonal antibodies, human antibodies,humanized antibodies and antibodies from non-human species, includinghuman antibodies derived from a human germline immunoglobulin sequencetransduced into the non-human species, e.g., mouse, sheep, chicken orgoat, recombinant antigen binding forms such as monobodies anddiabodies, multispecific antibodies (e.g. bispecific antibodies) formedfrom at least two full length antibodies (e.g., each portion comprisingthe antigen binding region of an antibody to a different antigen orepitope), and individual antigen binding fragments of any of theforegoing, e.g., of an antibody or the antibody from which it isderived, including dAbs, Fv, scFv, Fab, F(ab)′₂, Fab′.

The term “monoclonal antibody” as used herein refers to an antibodyobtained from a population of substantially homogeneous antibodies,i.e., the individual antibodies comprising the population are identicaland/or bind the same epitope. The modifier “monoclonal” indicates thecharacter of the antibody as being obtained from a substantiallyhomogeneous population of antibodies, and is not to be construed asrequiring production of the antibody by any particular method.

“Antigen binding fragments” of an antibody preferably comprise at leastthe variable regions of the heavy and/or light chains of an anti-α4β7antibody. For example, an antigen binding fragment of vedolizumab cancomprise amino acid residues 20-131 of the humanized light chainsequence of SEQ ID NO:2 and amino acid residues 20-140 of the humanizedheavy chain sequence of SEQ ID NO:1. Examples of such antigen bindingfragments include Fab fragments, Fab′ fragments, Fv fragments, scFv andF(ab′)₂ fragments. Antigen binding fragments of an antibody can beproduced by enzymatic cleavage or by recombinant techniques. Forinstance, papain or pepsin cleavage can be used to generate Fab orF(ab′)₂ fragments, respectively. Antibodies can also be produced in avariety of truncated forms using antibody genes in which one or morestop codons have been introduced upstream of the natural stop site. Forexample, a recombinant construct encoding the heavy chain of an F(ab′)₂fragment can be designed to include DNA sequences encoding the CH_(I)domain and hinge region of the heavy chain. In one aspect, antigenbinding fragments inhibit binding of α4β7 integrin to one or more of itsligands (e.g. the mucosal addressin MAdCAM (e.g., MAdCAM-1),fibronectin).

A “therapeutic monoclonal antibody” is an antibody used for therapy of ahuman subject. Therapeutic monoclonal antibodies disclosed hereininclude anti-α4β7 antibodies.

Antibody “effector functions” refer to those biological activitiesattributable to the Fc region (a native sequence Fc region or amino acidsequence variant Fc region) of an antibody. Examples of antibodyeffector functions include C1q binding; complement dependentcytotoxicity; Fc receptor binding; antibody-dependent cell-mediatedcytotoxicity (ADCC); phagocytosis; down regulation of cell surfacereceptors (e.g. B cell receptor; BCR), and the like. To assess ADCCactivity of a molecule of interest, an in vitro ADCC assay, such asthose described in U.S. Pat. Nos. 5,500,362 or 5,821,337 may beperformed.

Depending on the amino acid sequence of the constant domain of theirheavy chains, full length antibodies can be assigned to different“classes”. There are five major classes of full length antibodies: IgA,IgD, IgE, IgG, and IgM, and several of these may be further divided into“subclasses” (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA, and IgA2.The heavy-chain constant domains that correspond to the differentclasses of antibodies are called α, δ, ε, γ, and μ, respectively. Thesubunit structures and three-dimensional configurations of differentclasses of antibodies are well known.

The “light chains” of antibodies from any vertebrate species can beassigned to one of two clearly distinct types, called kappa (κ) andlambda (λ), based on the amino acid sequences of their constant domains.

The term “hypervariable region” when used herein refers to the aminoacid residues of an antibody which are responsible for antigen binding.The hypervariable region generally comprises amino acid residues from a“complementarity determining region” or “CDR” (e.g. residues 24-34 (L1),50-56 (L2) and 89-97 (L3) in the light chain variable domain and 31-35(H1), 50-65 (H2) and 95-102 (H3) in the heavy chain variable domain;Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed.Public Health Service, National Institutes of Health, Bethesda, Md.(1991)) and/or those residues from a “hypervariable loop” (e.g. residues26-32 (L1), 50-52 (L2) and 91-96 (L3) in the light chain variable domainand 26-32 (H1), 53-55 (H2) and 96-101 (H3) in the heavy chain variabledomain; Chothia and Lesk J. Mol. Biol. 196:901-917 (1987)). “FrameworkRegion” or “FR” residues are those variable domain residues other thanthe hypervariable region residues as herein defined. The hypervariableregion or the CDRs thereof can be transferred from one antibody chain toanother or to another protein to confer antigen binding specificity tothe resulting (composite) antibody or binding protein.

“Humanized” forms of non-human (e.g., rodent) antibodies are chimericantibodies that contain minimal sequence derived from the non-humanantibody. For the most part, humanized antibodies are humanimmunoglobulins (recipient antibody) in which residues from ahypervariable region of the recipient are replaced by residues from ahypervariable region of a non-human species (donor antibody) such asmouse, rat, rabbit or nonhuman primate having the desired specificity,affinity, and capacity. In some instances, framework region (FR)residues of the human antibody are replaced by corresponding non-humanresidues. Furthermore, humanized antibodies may comprise residues thatare not found in the recipient antibody or in the donor antibody. Thesemodifications are made to further refine antibody performance. Forfurther details, see Jones et al., Nature 321:522-525 (1986); Riechmannet al., Nature 332:323-329 (1988); and Presta, Curr. Op. Struct. Biol.2:593-596 (1992).

An “affinity matured” antibody has one or more alterations in one ormore hypervariable regions thereof which result an improvement in theaffinity of the antibody for antigen, compared to a parent antibodywhich does not possess those alteration(s). In one aspect, affinitymatured antibodies will have nanomolar or even picomolar affinities forthe target antigen. Affinity matured antibodies are produced byprocedures known in the art. Marks et al. Bio/Technology 10:779-783(1992) describes affinity maturation by VH and VL domain shuffling.Random mutagenesis of CDR and/or framework residues is described by:Barbas et al. Proc Nat. Acad. Sci, USA 91:3809-3813 (1994); Schier etal. Gene 169:147-155 (1995); Yelton et al. J. Immunol. 155:1994-2004(1995); Jackson et al., J. Immunol. 154(7):3310-9 (1995); and Hawkins etal., J. Mol. Biol. 226:889-896 (1992).

An “isolated” antibody is one which has been identified and separatedand/or recovered from a component of its natural environment. In certainembodiments, the antibody will be purified (1) to greater than 95% byweight of protein as determined by the Lowry method, and alternatively,more than 99% by weight, (2) to a degree sufficient to obtain at least15 residues of N-terminal or internal amino acid sequence by use of aspinning cup sequenator, or (3) to homogeneity by SDS-PAGE underreducing or non-reducing conditions using Coomassie blue or silverstain. Isolated antibody includes the antibody in situ withinrecombinant cells since at least one component of the antibody's naturalenvironment will not be present. Ordinarily, however, isolated antibodywill be prepared by at least one purification step.

“Treatment” refers to therapeutic treatment. Those in need of treatmentinclude those already with disease. Hence, the patient, e.g., human, tobe treated herein may have been diagnosed as suffering from a disease,such as an inflammatory bowel disease, e.g., Crohn's Disease orulcerative colitis. The terms “patient” and “subject” are usedinterchangeably herein.

“Prevention” refers to a treatment that results in the absence orreduction in the severity of an adverse event. In a population ofpatients, when treatment typically results in a certain percentage ofadverse events, or a certain percentage of adverse events that aresevere, but a treatment administered for prevention purposes insteadresults in a lower percentage of adverse events (i.e., a lower orreduced risk of adverse events) or a lower percentage of adverse eventsthat are severe (i.e., a lower or reduced risk that the adverse event issevere).

An anti-α4β7 antibody, vedolizumab, a humanized monoclonal antibody thathas binding specificity for the α₄β₇ integrin, is already indicated forthe treatment of patients with moderately to severely active ulcerativecolitis (UC) and Crohn's disease (CD). Vedolizumab has a novelgut-selective mechanism of action. By binding to cell surface-expressedα₄β₇, vedolizumab is an α4β7 antagonist and blocks a subset of memorygut-homing T lymphocytes from interacting with mucosal addressin celladhesion molecule-1 (MAdCAM-1) expressed on endothelial cells.

Several factors are associated with accelerated clearance of antibodiesincluding the presence of anti-drug antibodies, sex, body size,concomitant immunosuppressant use, disease type, albumin concentration,and degree of systemic inflammation. Furthermore, a consistentrelationship between efficacy and exposure, in distinction to drug dose,has been observed for many of these agents, such that higher trough drugconcentrations are associated with greater efficacy. Differences in drugclearance may be an important explanation for this observation. Forexample, cancer patients undergo immunosuppressive treatment of thetumor and treatment for infection. Therefore, an understanding of thedeterminants of clearance for therapeutic antibodies in transplantpatients may result in optimization of drug regimens.

In previous studies, single-dose pharmacokinetics, pharmacodynamics(α₄β₇ receptor saturation), safety, and tolerability of vedolizumab wereinvestigated over a dose range of 0.2 to 10 mg/kg in healthy volunteers(intravenous [IV] infusion) (unpublished data). After reaching peakconcentrations, vedolizumab serum concentrations fell in a generallybiexponential fashion until concentrations reached approximately 1 to 10ng/mL. Thereafter, concentrations appeared to fall in a nonlinearfashion. The multiple-dose pharmacokinetics and pharmacodynamics ofvedolizumab have been investigated following IV infusions of 0.5 and 2mg/kg in patients with CD and infusion of 2, 6, and 10 mg/kg in patientswith UC. Vedolizumab pharmacokinetics was generally linear following anIV infusion over the dose range of 2 to 10 mg/kg in patients with UC.After multiple-dose administration, rapid and near complete α₄β₇receptor saturation was achieved following the initial dose ofvedolizumab.

The efficacy and safety of vedolizumab induction and maintenance therapywere demonstrated in patients with CD in the GEMINI 2(ClinicalTrials.gov number, NCT00783692) and GEMINI 3(ClinicalTrials.gov number, NCT01224171) trials. The exposure-response(efficacy) relationships of vedolizumab in patients with CD forinduction and maintenance therapy have been presented elsewhere.

The TNF antagonist may be Adalimumab. Adalimumab is a recombinant humanIgG1 monoclonal antibody specific for human TNF-α. Adalimumab bindsspecifically to TNF-α and blocks its interaction with the p55 and p75cell surface TNF-α receptors. Adalimumab also lyses surface TNF-αexpressing cells in vitro in the presence of complement. Adalimumab doesnot bind or inactivate lymphotoxin (TNF-β). TNF-α is a naturallyoccurring cytokine that is involved in normal inflammatory and immuneresponses. TNF-α plays an important role in both the pathologicinflammation and the joint destruction that are hallmarks ofinflammatory disease. Adalimumab also modulates biological responsesthat are induced or regulated by TNF-α, including changes in the levelsof adhesion molecules responsible for leukocyte migration.

Adalimumab is approved globally for the treatment of moderately toseverely active CD in patients who have had an inadequate response toconventional therapy. Additionally, adalimumab is approved for reducingsigns and symptoms and inducing clinical remission in these patients ifthey have also lost response to or are intolerant to infliximab.

Adalimumab 40 mg weekly or every other week has been shown to beeffective for maintaining clinical remission in patients with CD whohave responded to adalimumab induction therapy. Adalimumab has also beenshown to have corticosteroid-sparing effects in patients with CD (Behm BW B S. Cochrane Database of Systematic Reviews 2008(1)).

The immunomodulator may be an antimetabolite. Methotrexate is anantimetabolite that is approved for the treatment of certain neoplasticdiseases, severe psoriasis, and adult rheumatoid arthritis. Methotrexatewas originally developed as an antineoplastic, and is an inhibitor ofthe enzyme dihydrofolate reductase, which catalyzes a reaction in theproduction of tetrahydrofolic acid. This pathway is essential to thesynthesis of the purine and pyrimidine components of deoxyribonucleicacid (DNA), and thus the drug slows cellular division. Although themechanism of action of low-dose methotrexate in the treatment ofautoimmune disease is not well understood, there is evidence supportingboth immunosuppressive and anti-inflammatory effects.

Treatment of Inflammatory Bowel Disease with Triple Combination Therapy

The invention relates to a method of treating inflammatory bowel disease(e.g., Crohn's Disease (CD) or ulcerative colitis) in a patient using atriple combination therapy. The human patient may be an adult (e.g., 18years or older), an adolescent, or a child. The triple combinationtherapy may improve remission rates and modify disease progression byincluding agents with different mechanisms of action, particularly forpatients who are at higher risk for CD complications. Patients whorespond to treatment with infliximab or adalimumab have been shown tohave a decrease in MAdCAM and an increase in α4β7-positive cells(Biancheri P, et al. Inflamm Bowel Dis 2013; 19(2):259-64). Thus, theirvedolizumab pathway is active, and the addition of vedolizumab to thetherapy regimen can provide clinically relevant synergy.

In one embodiment, the triple combination therapy of the invention isused to treat patients who are at high risk for developing complicationsfrom inflammatory bowel disease. For example, patients at high risk fordeveloping complications from CD, or aggressive CD, may include thosepatients with involvement of the upper GI tract and ileum, penetratingdisease, early age at diagnosis, smoking, extensive ulceration of themucosa, high titers of serum antibodies, use of corticosteroids atdiagnosis, and mutations of the NOD2 gene. Patients at high risk fordeveloping complications of CD may be defined as described above for thePROSPECT algorithm or the AGA criteria. Patients identified as high riskCD patients can be targeted for triple combination therapy. The patienttargeted for triple combination therapy may have a Simple EndoscopicScore for Crohn's Disease (SES-CD) of ≥7 or ≥4 if isolated ilealdisease. The patient targeted for triple combination therapy may haveactive disease as judged by the Crohn's Disease Activity Index (CDAI) of≥220. The CDAI score weighs factors including the number of liquid orvery soft stools, the severity of abdominal pain, general well being,extra-intestinal manifestations of the disease, such as arthritis,iritis, erythemia, fistula or abscess or fever, whether the patient istaking an antidiarrheal medication, abdominal mass, hematocrit and bodyweight.

Anti-Integrin

An anti-integrin, such as an anti-α4β7 antibody, is administered in aneffective amount which inhibits binding of α4β7 integrin to a ligandthereof. For therapy, an effective amount will be sufficient to achievethe desired effect (e.g., inducing endoscopic remission, inducingmucosal healing, achieving clinical remission, achieving biomarkerremission). An α4β7 antagonist, such as an anti-α4β7 antibody may beadministered in a unit dose or multiple doses. The dosage can bedetermined by methods known in the art and can be dependent, forexample, upon the individual's age, sensitivity, tolerance and overallwell-being. Examples of modes of administration include topical routessuch as nasal or inhalational or transdermal administration, enteralroutes, such as through a feeding tube or suppository, and parenteralroutes, such as intravenous, intramuscular, subcutaneous, intraarterial,intraperitoneal, or intravitreal administration. Suitable dosages forantibodies can be from about 0.1 mg/kg body weight to about 10.0 mg/kgbody weight per treatment, for example about 2 mg/kg to about 7 mg/kg,about 3 mg/kg to about 6 mg/kg, or about 3.5 to about 5 mg/kg. Inparticular embodiments, the dose administered is about 0.3 mg/kg, about0.5 mg/kg, about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg,about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9mg/kg, or about 10 mg/kg. In some embodiments, vedolizumab isadministered at a dose of 50 mg, 75 mg, 100 mg, 300 mg, 450 mg, 500 mgor 600 mg. In some embodiments, vedolizumab is administered at a dose of108 mg, 90 to 120 mg, 216 mg, 160 mg, 165 mg, 155 to 180 mg, 170 mg or180 mg. In some embodiments, the anti-α4β7 antibody, such as vedolizumabis provided as a dry, lyophilized formulation which can be reconstitutedwith a liquid, such as sterile water, for administration. Administrationof a reconstituted formulation can be by parenteral injection by one ofthe routes described above. An intravenous injection can be by infusion,such as by further dilution with sterile isotonic saline, buffer, e.g.,phosphate-buffered saline or Ringer's (lactated or dextrose) solution.In some embodiments, the anti-α4β7 antibody is administered bysubcutaneous injection, e.g., a dose of about 108 mg or about 165 mg orabout 216 mg, at about every two, three or four weeks after the start oftherapy or after the third subsequent dose.

The anti-integrin, which is an anti-α4β7 antibody, can bind to anepitope on the α4 chain (e.g., humanized MAb 21.6 (Bendig et al., U.S.Pat. No. 5,840,299), on the (β7 chain (e.g., FIB504 or a humanizedderivative (e.g., Fong et al., U.S. Pat. No. 7,528,236)), or to acombinatorial epitope formed by the association of the α4 chain with theβ7 chain. AMG-181 or other antibodies described in US 2010/0254975 areanti-α4β7 antibodies. In one aspect, the antibody binds a combinatorialepitope on the α4β7 complex, but does not bind an epitope on the α4chain or the β7 chain unless the chains are in association with eachother. The association of α4 integrin with β7 integrin can create acombinatorial epitope for example, by bringing into proximity residuespresent on both chains which together comprise the epitope or byconformationally exposing on one chain, e.g., the α4 integrin chain orthe β7 integrin chain, an epitopic binding site that is inaccessible toantibody binding in the absence of the proper integrin partner or in theabsence of integrin activation. In another aspect, the anti-α4β7antibody binds both the α4 integrin chain and the β7 integrin chain, andthus, is specific for the α4β7 integrin complex. Such antibodies canbind α4β7 but not bind α4β1, and/or not bind α_(E)β7, for example. Inanother aspect, the anti-α4β7 antibody binds to the same orsubstantially the same epitope as the Act-1 antibody (Lazarovits, A. I.et al., J. Immunol., 133(4): 1857-1862 (1984), Schweighoffer et al., J.Immunol., 151(2): 717-729, 1993; Bednarczyk et al., J. Biol. Chem.,269(11): 8348-8354, 1994). Murine ACT-1 Hybridoma cell line, whichproduces the murine Act-1 monoclonal antibody, was deposited under theprovisions of the Budapest Treaty on Aug. 22, 2001, on behalf MillenniumPharmaceuticals, Inc., 40 Landsdowne Street, Cambridge, Mass. 02139,U.S.A., at the American Type Culture Collection, 10801 UniversityBoulevard, Manassas, Va. 20110-2209, U.S.A., under Accession No.PTA-3663. In another aspect, the anti-α4β7 antibody is a human antibodyor an α4β7 binding protein using the CDRs provided in U.S. PatentApplication Publication No. 2010/0254975.

In one aspect, the anti-integrin is an anti-MAdCAM antibody (see e.g.,U.S. Pat. No. 8,277,808, PF-00547659 or antibodies described inWO2005/067620), or an engineered form of a ligand, such as a MAdCAM-Fcchimera such as described in U.S. Pat. No. 7,803,904.

In one aspect, the anti-integrin inhibits binding of α4β7 to one or moreof its ligands (e.g. the mucosal addressin, e.g., MAdCAM (e.g.,MAdCAM-1), fibronectin, and/or vascular addressin (VCAM)). PrimateMAdCAMs are described in the PCT publication WO 96/24673, the entireteachings of which are incorporated herein by this reference. In anotheraspect, the anti-integrin inhibits binding of α4β7 to MAdCAM (e.g.,MAdCAM-1) and/or fibronectin without inhibiting the binding of VCAM.

In one aspect, the anti-integrin, e.g., an anti-α4β7 antibody, has thebinding specificity, e.g., comprises the complementarity determiningregions of mouse Act-1 antibody. For example, an anti-α4β7 antibodycomprises a heavy chain that contains the 3 heavy chain complementaritydetermining regions (CDRs, CDR1, SEQ ID NO:4, CDR2, SEQ ID NO:5 andCDR3, SEQ ID NO:6) of the mouse Act-1 antibody and suitable human heavychain framework regions; and also comprises a light chain that containsthe 3 light chain CDRs (CDR1, SEQ ID NO:7, CDR2, SEQ ID NO:8 and CDR3,SEQ ID NO:9) of the mouse Act-1 antibody and suitable human light chainframework regions. In some embodiments the anti-α4β7 antibody is an IgG1isotype.

In one aspect, the anti-integrin for use in the treatments are humanizedversions of the mouse Act-1 antibody. Suitable methods for preparinghumanized antibodies are well-known in the art. Generally, the humanizedanti-α4β7 antibody will contain a heavy chain that contains the 3 heavychain complementarity determining regions (CDRs, CDR1, SEQ ID NO:4,CDR2, SEQ ID NO:5 and CDR3, SEQ ID NO:6) of the mouse Act-1 antibody andsuitable human heavy chain framework regions; and also contain a lightchain that contains the 3 light chain CDRs (CDR1, SEQ ID NO:7, CDR2, SEQID NO:8 and CDR3, SEQ ID NO:9) of the mouse Act-1 antibody and suitablehuman light chain framework regions. The humanized Act-1 antibody cancontain any suitable human framework regions, including consensusframework regions, with or without amino acid substitutions. Forexample, one or more of the framework amino acids can be replaced withanother amino acid, such as the amino acid at the corresponding positionin the mouse Act-1 antibody. The human constant region or portionthereof, if present, can be derived from the κ or λ light chains, and/orthe γ (e.g., γ1, γ2, γ3, γ4), μ, α (e.g., α1, α2), δ or ε heavy chainsof human antibodies, including allelic variants. A particular constantregion (e.g., IgG1), variant or portions thereof can be selected inorder to tailor effector function. For example, a mutated constantregion (variant) can be incorporated into a fusion protein to minimizebinding to Fc receptors and/or ability to fix complement (see e.g.,Winter et al., GB 2,209,757 B; Morrison et al., WO 89/07142; Morgan etal., WO 94/29351, Dec. 22, 1994). Humanized versions of Act-1 antibodywere described in PCT publications nos. WO98/06248 and WO07/61679, theentire teachings of each of which are incorporated herein by thisreference. Treatment methods using anti-α4β7 integrin antibodies aredescribed in publication nos. U.S. 2005/0095238, U.S. 2005/0095238,WO2012151248 and WO 2012/151247.

In one aspect, the anti-integrin is the anti-α4β7 antibody, vedolizumab.Vedolizumab IV (also called MLN0002, ENTYVIO™ or KYNTELES™) is ahumanized antibody (Ig) G1 mAb directed against the human lymphocyteintegrin α4β7. The α4β7 integrin mediates lymphocyte trafficking to GImucosa, gut-associated lymphoid tissue (GALT) and mesenteric lymph nodesthrough adhesive interaction with mucosal addressin cell adhesionmolecule-1 (MAdCAM-1), which is expressed on the endothelium ofmesenteric lymph nodes and GI mucosa. Vedolizumab binds the α4β7integrin, antagonizes its adherence to MAdCAM-1 and as such, impairs themigration of naïve T cells to the GALT and mesenteric lymph nodes andgut homing leukocytes into GI mucosa.

In another aspect, the anti-integrin is a humanized anti-α4β7 antibodyfor use in the treatment and comprises a heavy chain variable regioncomprising amino acids 20 to 140 of SEQ ID NO:1, and a light chainvariable region comprising amino acids 20 to 131 of SEQ ID NO:2 or aminoacids 1 to 112 of SEQ ID NO:3. If desired, a suitable human constantregion(s) can be present. For example, the humanized anti-α4β7 antibodycan comprise a heavy chain that comprises amino acids 20 to 470 of SEQID NO:1 and a light chain comprising amino acids 1 to 219 of SEQ IDNO:3. In another example, the humanized anti-α4β7 antibody can comprisea heavy chain that comprises amino acids 20 to 470 of SEQ ID NO:1 and alight chain comprising amino acids 20 to 238 of SEQ ID NO:2. Vedolizumabis cataloged under Chemical Abstract Service (CAS, American ChemicalSociety) Registry number 943609-66-3).

Substitutions to the humanized anti-α4β7 antibody sequence can be, forexample, mutations to the heavy and light chain framework regions, suchas a mutation of isoleucine to valine on residue 2 of SEQ ID NO:10; amutation of methionine to valine on residue 4 of SEQ ID NO:10; amutation of alanine to glycine on residue 24 of SEQ ID NO:11; a mutationof arginine to lysine at residue 38 of SEQ ID NO:11; a mutation ofalanine to arginine at residue 40 of SEQ ID NO:11; a mutation ofmethionine to isoleucine on residue 48 of SEQ ID NO:11; a mutation ofisoleucine to leucine on residue 69 of SEQ ID NO:11; a mutation ofarginine to valine on residue 71 of SEQ ID NO:11; a mutation ofthreonine to isoleucine on residue 73 of SEQ ID NO:11; or anycombination thereof; and replacement of the heavy chain CDRs with theCDRs (CDR1, SEQ ID NO:4, CDR2, SEQ ID NO:5 and CDR3, SEQ ID NO:6) of themouse Act-1 antibody; and replacement of the light chain CDRs with thelight chain CDRs (CDR1, SEQ ID NO:7, CDR2, SEQ ID NO:8 and CDR3, SEQ IDNO:9) of the mouse Act-1 antibody.

The dose can be administered to the patient over about 20 minutes, about25 minutes, about 30 minutes, about 35 minutes, or about 40 minutes. Insome embodiments, the dose can be administered to the patient for up totwo hours.

TNF Antagonist

The invention features a triple combination therapy which includesadministration of a TNF antagonist for the treatment of an inflammatorybowel disease. A TNF antagonist is administered in an effective amountwhich inhibits binding TNF-α and blocks its interaction with the p55 andp75 cell surface TNF-α receptors. Suitable TNF antagonists include, forexample, adalimumab, infliximab, etanercept, golimumab, certolizumabpegol, biosimilars thereof and equivalents thereof. For therapy, aneffective amount will be sufficient to achieve the desired effect (e.g.,inducing endoscopic remission, inducing mucosal healing, achievingclinical remission, achieving biomarker remission). A TNF antagonist,such as an anti-TNF-α antibody (e.g., adalimumab) may be administered ina unit dose or multiple doses. The dosage can be determined by methodsknown in the art and can be dependent, for example, upon theindividual's age, sensitivity, tolerance and overall well-being.Examples of modes of administration include topical routes such as nasalor inhalational or transdermal administration, enteral routes, such asthrough a feeding tube or suppository, and parenteral routes, such asintravenous, intramuscular, subcutaneous, intraarterial,intraperitoneal, or intravitreal administration. Suitable dosages forantibodies can be from about 0.1 mg/kg body weight to about 10.0 mg/kgbody weight per treatment, for example about 1 mg/kg to about 8 mg/kg,about 2 mg/kg to about 7 mg/kg, about 3 mg/kg to about 6 mg/kg, or about3.5 to about 5 mg/kg. In particular embodiments, the dose administeredis about 0.3 mg/kg, about 0.5 mg/kg, about 1 mg/kg, about 2 mg/kg, about3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg,about 8 mg/kg, about 9 mg/kg, or about 10 mg/kg. In some embodiments,the TNF antagonist is administered at a dose of 40 mg, 50 mg, 75 mg, 80mg, 100 mg, 150 mg, 160 mg, 175 mg, 200 mg, 300 mg, 400 mg, 450 mg, 500mg or 600 mg. In some embodiments, the TNF antagonist is administered ata dose of 40 mg, 80 mg, 160 mg, 80 to 200 mg, 170 mg, 165 mg, 155 mg,150 to 180 mg, 140 mg or 130 mg.

In one embodiment, the triple combination therapy of the inventionincludes the use of adalimumab for the treatment of an inflammatorybowel disease. Adalimumab may be administered to a patient having aninflammatory bowel disease, such as Crohn's disease or ulcerativecolitis. In one embodiment, adalimumab is subcutaneously administered toa subject having Crohn's disease or ulcerative colitis at an initialdose of 160 mg at week 0, followed by a second dose of 80 mg at week 2,followed by a 40 dose at week 4 and every two weeks thereafter. In oneembodiment, the triple combination therapy comprises discontinuingadalimumab at week 26 of treatment in the patient.

In one embodiment, the triple combination therapy of the inventionincludes the use of infliximab for the treatment of an inflammatorybowel disease, such as Crohn's disease or ulcerative colitis. In oneembodiment, infliximab is intravenously administered to a subject havingCrohn's disease or ulcerative colitis at a dose of 5 mg/kg at weeks 0, 2and 6 weeks, and then every 8 weeks thereafter. In one embodiment, thetriple combination therapy comprises discontinuing inflixmab at week 26of treatment in the patient.

In one embodiment, the triple combination therapy of the inventionincludes the use of golimumab for the treatment of an inflammatory boweldisease, such as Crohn's disease or ulcerative colitis. In oneembodiment, golimumab is subcutaneously administered to a subject havingCrohn's disease or ulcerative colitis at a dose of 200 mg at week 0,followed by a 100 mg dose a week 2, followed by a 100 mg dose every 4weeks thereafter. In one embodiment, the triple combination therapycomprises discontinuing golimumab at week 26 of treatment in thepatient.

In one embodiment, the triple combination therapy of the inventionincludes the use of certolizumab pegol for the treatment of aninflammatory bowel disease, such as Crohn's disease or ulcerativecolitis. In one embodiment, certolizumab pegol is subcutaneouslyadministered to a subject having Crohn's disease or ulcerative colitisat a dose of 400 mg at week 0, followed by 400 mg doses at weeks 2 and4. If a response occurs, then 400 mg of certolizumab pegol isadministered every four weeks thereafter. In one embodiment, the triplecombination therapy comprises discontinuing certolizumab pegol at week26 of treatment in the patient.

Immunomodulators

An immunomodulator is administered in an effective amount to reduceimmunogenicity. Examples of suitable immunomodulators includefluorouracil, cladribine, capecitabline, methotrexate, pemetrexed,mercaptopurine, hydroxyurea, gemcitabine, fludarabine, pralatrexate,clofarabine, cytarabine, decitabine, floxuridine, nelarabine, andthioguanine. In one embodiment the immunomodulator is methotrexate. Fortherapy, an effective amount will be sufficient to achieve the desiredeffect (e.g., inducing endoscopic remission, inducing mucosal healing,achieving clinical remission, achieving biomarker remission). Animmunomodulator, such as an antimetabolite (e.g., methotrexate) may beadministered in a unit dose or multiple doses. The dosage can bedetermined by methods known in the art and can be dependent, forexample, upon the individual's age, sensitivity, tolerance and overallwell-being. Examples of modes of administration include oraladministration, topical routes such as nasal or inhalational ortransdermal administration, enteral routes, such as through a feedingtube or suppository, and parenteral routes, such as intravenous,intramuscular, subcutaneous, intraarterial, intraperitoneal, orintravitreal administration. Suitable dosages for immunomodulators canbe a dose of 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, or 45 mg. In someembodiments, methotrexate is administered at a dose of 10 mg, 15 mg, 20mg, 10 to 30 mg, 25 mg, 30 mg, or 45 mg.

The dose of the immunomodulator, e.g., methotrexate, can be administeredto the patient daily, weekly, or monthly. In some embodiments, the dosecan be administered to the patient orally weekly for up to 34 weeks.

The triple combination therapy, such as anti-integrin/TNFantagonist/immunomodulator, may be administered to an individual (e.g.,a human) in series, in parallel, or simultaneously. The triplecombination therapy may be administered to an individual by a singleroute of administration, by two different routes of administration, orby three different routes of administration.

In one embodiment, the dosing regimen comprises administration of 300 mgof the anti-integrin by intravenous infusion at Weeks 0, 2, 6, and thenevery 8 weeks thereafter; administration of 160 mg of the TNFantagonist, e.g., adalimumab, by subcutaneous injection at Week 0,administration of 80 mg of the TNF antagonist, e.g., adalimumab, at Week2, and then 40 mg of the TNF antagonist, e.g., adalimumab, every 2 weeksthereafter; and oral administration of 15 mg of the immunomodulator,e.g., methotrexate, weekly.

In one embodiment, the method comprises administering an effectiveamount of the triple combination therapy to a patient. If the triplecombination therapy, or any component of the triple combination therapy,is in a formulation which is in a solid, e.g., dry state, the process ofadministration can comprise a step of converting the formulation to aliquid state. In one aspect, a dry formulation can be reconstituted,e.g., by a liquid as described above, for use in injection, e.g.intravenous, intramuscular or subcutaneous injection. In another aspect,a solid or dry formulation can be administered topically, e.g., in apatch, cream, aerosol or suppository.

In one embodiment, the present invention provides a method for treatinga high risk CD patient with triple combination therapy. The methodcomprises the steps of administering an initial 300 mg dose of ananti-integrin to a high risk CD patient, administering a subsequentanti-integrin 300 mg dose two weeks after the initial dose,administering a second subsequent anti-integrin 300 mg dose six weeksafter the initial dose, and subsequent 300 mg doses every eight weeksthereafter, administering an initial 160 mg dose of a TNF antagonist,followed by a subsequent 80 mg dose of TNF antagonist two weeks afterthe initial dose, and subsequent 40 mg doses of TNF antagonist every twoweeks thereafter, and administering a 15 mg methotrexate dose weeklybeginning at Week 0.

The invention provides a triple combination therapy for use in treatingan inflammatory bowel disease, such as CD or UC, in a patient havinghigh risk of complications related to the inflammatory bowel disease,such as CD or UC, the use comprising administering an initial dose ofanti-integrin, two weeks after the initial dose, and six weeks after theinitial dose, and every eight weeks thereafter for a total of 102 weeks;administering an initial dose of TNF antagonist, half the initial dosetwo weeks after the initial dose, and a quarter of the initial doseevery two weeks thereafter for a total of 26 weeks; and administering aweekly dose of an immunomodulator for 34 weeks. In some embodiments, theanti-integrin is vedolizumab. In some embodiments the TNF modulator isadalimumab. In some embodiments the immunomodulator is methotrexate. Insome embodiments the triple combination therapy includes administrationof vedolizumab, adalimumab, and methotrexate. In some embodiments thetriple combination therapy includes vedolizumab, a TNF antagonist, andmethotrexate. In some embodiments the triple combination therapyincludes vedolizumab, a TNF antagonist, and an immunomodulator. In someembodiments the triple combination therapy includes an anti-α4β7antibody, a TNF antagonist, and methotrexate.

In one embodiment, the dosing regimen comprises administration of 300 mgof vedolizumab by intravenous infusion at Weeks 0, 2, 6, and then every8 weeks thereafter; administration of 160 mg of adalimumab bysubcutaneous injection at Week 0, administration of 80 mg of adalimumabat Week 2, and then 40 mg of the adalimumab every 2 weeks thereafter;and oral administration of 15 mg of methotrexate weekly.

In some embodiments, the IBD, e.g., CD, has an exacerbation after 26weeks, e.g., as defined by a CDAI increase of >70 from the prior visiton two occasions two weeks apart and disease activity as seen bycolonoscopy and a CRP value above normal (>5 mg/L); or fecalcalprotectin >250 μg/g. In an embodiment of exacerbation of IBD, 300 mgvedolizumab may be administered every 4 weeks.

The triple combination therapy may further comprise a corticosteroidtapering regimen, such as beginning about 1 to 3 weeks or about twoweeks after starting triple combination therapy. In some embodiments, ahigh risk IBD patient may be undergoing prior therapy withcorticosteroids, such as prednisone, e.g. 10 to 20 mg/day, 20 to 40mg/day, 25 to 35 mg/day or about 30 mg/day, or budesonide, e.g., 2 to 12mg/day, 3 to 10 mg/day or about 9 mg/day, at diagnosis or at Baseline.For prednisone, the dose may be reduced at a rate of 5 mg/week until 5mg/day is reached, then the dose of prednisone is reduced at a rate of2.5 mg/week until discontinuation. For budesonide, the dose is reducedat a rate of 3 mg every 2 weeks until discontinuation.

In some embodiments, the triple combination therapy of a high riskpatient results in endoscopic remission of the inflammatory boweldisease. “Endoscopic remission” as used herein, refers to a conditionwith a low endoscopic score. An example of a method to assess theendoscopic score in ulcerative colitis is flexible sigmoidoscopy. Theendoscopic score in ulcerative colitis can be the Mayo subscore. Anexample of a method to assess the endoscopic score in Crohn's disease isileocolonoscopy. The endoscopic score in Crohn's disease can be thesimple endoscopic score for Crohn's Disease (SES-CD). The SES-CD caninclude measures such as the size of ulcers, the amount of ulceratedsurface, the amount of affected surface and whether and to what extentthe alimentary canal is narrowed.

In an embodiment, a high risk Crohn's disease triple combination therapypatient achieves endoscopic remission as defined by a SES-CD score of 0to 2 by week 26, or by weeks 22 to 30 or weeks 24 to 28 of treatment. Inother embodiments, the triple combination therapy of the inventionresults in a degree of response or remission selected from the groupconsisting of SES-CD ≤4 and reduction from baseline SES-CD of at least 2points and no individual SES-CD subscore >1 at Week 26; 50% reduction inSES-CD from Baseline at week 26; deep remission (defined as CDAI <150and SES-CD 0-2) at week 26; clinical remission (defined as CDAI <150)and endoscopic response as a measure of mucosal healing (defined as 50%reduction in SES-CD from Baseline) at week 26; clinical remission (CDAIscore <150) at Weeks 10 and 26; clinical response (defined as ≥100-pointdecrease in CDAI score) at Weeks 10 and 26; clinical remission (definedas CDAI <150) and C-reactive protein (CRP)<5 mg/L (in subjects withelevated CRP at Baseline) at Weeks 26, 52, 78, and 102; anddiscontinuation of Baseline corticosteroid use and clinical remission(CDAI score <150) at Weeks 10, 26, and 102.

In some embodiments, a high risk Crohn's disease triple combinationtherapy patient achieves long-term benefit. In one embodiment, thetriple combination therapy of the invention results in maintainingclinical remission (defined as CDAI <150) at Weeks 52, 78, and 102. Inanother embodiment, the triple combination therapy of the inventionresults in maintaining endoscopic remission defined as SES-CD 0-2 atWeek 102. In another embodiment, the triple combination therapy of theinvention results in maintaining deep remission (defined as CDAI <150and SES-CD 0-2) at Week 102. In other embodiments, the triplecombination therapy of the invention results in a degree of long termbenefit selected from the group consisting of maintaining endoscopichealing defined as SES-CD ≤4 and reduction from baseline SES-CD of atleast 2 points and no individual SES-CD subscore >1 at Week 102;maintaining endoscopic response defined as 50% reduction in SES-CD fromBaseline at Week 102; maintaining clinical remission (defined as CDAI<150) and endoscopic response as a measure of mucosal healing (definedas 50% reduction in SES-CD from baseline) at Week 102; achievingnormalization of CRP defined as <5 mg/L at Week 26 (in those elevated atBaseline); and achieving a Patient-reported outcome 2 (PRO-2) score ≤75(a subset of the CDAI score and derived from a combination of liquid orvery soft stools (multiplied by 2) and abdominal pain severity ((on ascale of 0 to 3) multiplied by 5) over averaged over the prior 7 days)and an SES-CD ≤4 and a reduction from baseline SES-CD of at least 2points and no individual SES-CD subscore >1 at Weeks 26 and 102.

High Risk Crohn's Disease Patients

In one embodiment, the triple combination therapy disclosed herein isused to treat a subpopulation of Crohn's disease patients who are atrisk for developing complications following diagnosis. Such high riskpatients may be identified using predictive methods known in the art,including, for example, the PROSPECT predictive method. As described inSiegel et al. (2016) Aliment Pharmacol Ther 43: 262-271, the PROSPECTpredictive test is based on clinical, serologic and genetic variables ofthe patient, and is used to determine the likelihood that a CD patientwill have a disease complication by year 2 of diagnosis. A high risk CDpatient is one who has at least a 20% chance of such a complication byyear 2, as determined by, for example, the PROSPECT predictive method.

High Risk Ulcerative Colitis Disease Patients

In one embodiment, the triple combination therapy disclosed herein isused to treat a subpopulation of UC disease patients who are at risk fordeveloping complications following diagnosis. Such high risk UC patientsare understood to be at an increased risk for colectomy. High risk UCpatents may also be identified by their failure to maintainsteroid-induced remission.

The invention will be more fully understood by reference to thefollowing examples. They should not, however, be construed as limitingthe scope of the invention. All literature and patent citations areincorporated herein by reference.

EXEMPLIFICATION Example 1

A phase 4, open-label, multicenter study in subjects withnewly-diagnosed CD at higher risk for complications due to aggressivedisease is designed to evaluate the safety, tolerability, and clinicalactivity of triple combination therapy (300 mg vedolizumab IV, 160/80/40mg adalimumab SC, and 15 mg oral methotrexate). A predictive toolincorporating clinical, serological, and genetic variables will be usedto stratify which subjects are at higher risk for developingcomplications. The study will run over a 26-week treatment period forinduction of endoscopic remission and mucosal healing followed byefficacy and safety of vedolizumab IV monotherapy to maintain remissionfor 76 weeks, for a total treatment period of 102 weeks.

Patients are eligible for the study if they have been diagnosed with CDwithin the previous 18 months, and are naïve to biologics. Patients whomeet all eligibility criteria and provide written informed consent areenrolled in this study.

Patients are excluded from the study if they are at low risk for CDcomplications as calculated by the CD PROSPECT predictive tool, have anyevidence of active infection during screening, have a history of anybacterial, viral, and other infection due to opportunistic pathogens,have had any prior exposure to any TNF antagonist biologic therapy, orto vedolizumab, natalizumab, efalizumab, or rituximab, have any priorCD-related surgery or CD complication requiring surgery, have a historyof tuberculosis, lymphoma, lymphoproliferative disease, or congestiveheart failure or unstable angina. Patients with a medical history thatcontradicts the use of methotrexate or adalimumab or indicatesintolerance to methotrexate or adalimumab are also excluded.

The study consists of up to a 4-week screening period, a 26-weekcombination treatment period, an additional 76-week vedolizumab IVmonotherapy treatment period, and a 26-week follow-up period followinglast dose (with final efficacy evaluations at week 120). The duration ofthe study from Screening to final efficacy visit at Week 120 will beapproximately 124 weeks. All subjects will participate in safetyfollow-up telephone calls 18 and 26 weeks after last dose, for a totalfollow-up of 128 weeks. Subjects who discontinue early will alsoparticipate in safety follow-up telephone calls 18 and 26 weeks aftertheir last dose. The primary endpoint will be subjects achievingendoscopic remission (defined as Simple Endoscopic Score for Crohn'sDisease (SES-CD) 0-2) at Week 26. The SES-CD evaluates 4 endoscopicvariables (ulcer size, proportion of the surface area that is ulcerated,proportion of the surface area affected, and stenosis) by scoring eachvariable on a scale from 0 to 3 where higher scores indicate more severedisease, in 5 colonic segments (ileum, right colon, transverse colon,left colon, and rectum). The score for each endoscopic variable is thesum of the values obtained for each segment. The SES-CD Total is the sumof the 4 endoscopic variable scores from 0 to 56.

Vital signs, physical and neurological examinations, adverse event (AE)assessments, and laboratory values (chemistry, hematology, andurinalysis) are obtained to evaluate the safety and tolerability of thetriple combination therapy. To exclude patients with progressivemultifocal leukoencephalopathy (PML), a Risk Assessment and Minimizationfor PML (RAMP) questionnaire is administered at Screening and prior todosing at each visit, to evaluate symptoms suggestive of PML.

SEQUENCE LISTING SEQ ID NO: 1 Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly 1               5                   10                  15 Val His Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys             20                  25                  30 Pro Gly Ala Ser Val Lys Val Ser Cys Lys Gly Ser Gly Tyr Thr Phe         35                  40                  45 Thr Ser Tyr Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu     50                  55                  60 Glu Trp Ile Gly Glu Ile Asp Pro Ser Glu Ser Asn Thr Asn Tyr Asn 65                  70                  75                  80 Gln Lys Phe Lys Gly Arg Val Thr Leu Thr Val Asp Ile Ser Ala Ser                 85                  90                  95 Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val             100                 105                 110 Tyr Tyr Cys Ala Arg Gly Gly Tyr Asp Gly Trp Asp Tyr Ala Ile Asp         115                 120                 125 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys     130                 135                 140 Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly 145                 150                 155                 160 Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro                 165                 170                 175 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr             180                 185                 190 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val         195                 200                 205 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn     210                 215                 220 Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro 225                 230                 235                 240 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu                 245                 250                 255 Leu Ala Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp             260                 265                 270 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp         275                 280                 285 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly     290                 295                 300 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 305                 310                 315                 320 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp                 325                 330                 335 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro             340                 345                 350 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu         355                 360                 365 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn     370                 375                 380 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 385                 390                 395                 400 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr                 405                 410                 415 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys             420                 425                 430 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys         435                 440                 445 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu     450                 455                 460 Ser Leu Ser Pro Gly Lys  465                 470  SEQ ID NO: 2 Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly 1               5                   10                  15 Val His Ser Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val             20                  25                  30 Thr Pro Gly Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu         35                  40                  45 Ala Lys Ser Tyr Gly Asn Thr Tyr Leu Ser Trp Tyr Leu Gln Lys Pro     50                  55                  60 Gly Gln Ser Pro Gln Leu Leu Ile Tyr Gly Ile Ser Asn Arg Phe Ser 65                  70                  75                  80 Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr                 85                  90                  95 Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys             100                 105                 110 Leu Gln Gly Thr His Gln Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val         115                 120                 125 Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro     130                 135                 140 Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu 145                 150                 155                 160 Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn                 165                 170                 175 Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser             180                 185                 190 Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala         195                 200                 205 Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly     210                 215                 220 Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 225                 230                 235  SEQ ID NO: 3 Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly 1               5                   10                  15 Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Ala Lys Ser             20                  25                  30 Tyr Gly Asn Thr Tyr Leu Ser Trp Tyr Leu Gln Lys Pro Gly Gln Ser         35                  40                  45 Pro Gln Leu Leu Ile Tyr Gly Ile Ser Asn Arg Phe Ser Gly Val Pro     50                  55                  60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65                  70                  75                  80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Leu Gln Gly                 85                  90                  95 Thr His Gln Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys             100                 105                 110 Arg Ala Asp Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu         115                 120                 125 Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe     130                 135                 140 Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln 145                 150                 155                 160 Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser                 165                 170                 175 Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu             180                 185                 190 Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser         195                 200                 205 Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys     210                 215  SEQ ID NO: 4  Ser Tyr Trp Met His 1               5  SEQ ID NO: 5 Glu Ile Asp Pro Ser Glu Ser Asn Thr Asn Tyr Asn Gln Lys Phe Lys 1               5                   10                  15  Gly SEQ ID NO: 6  Gly Gly Tyr Asp Gly Trp Asp Tyr Ala Ile Asp Tyr 1               5                   10  SEQ ID NO: 7 Arg Ser Ser Gln Ser Leu Ala Lys Ser Tyr Gly Asn Thr Tyr Leu Ser 1               5                   10                  15 SEQ ID NO: 8  Gly Ile Ser Asn Arg Phe Ser  1               5 SEQ ID NO: 9  Leu Gln Gly Thr His Gln Pro Tyr Thr  1               5 SEQ ID NO: 10 Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly 1               5                   10                  15 Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser             20                  25                  30 Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser         35                  40                  45 Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro     50                  55                  60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65                  70                  75                  80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala                 85                  90                  95 Leu Gln Thr Pro Gln Thr Phe Gly Gln Gly Lys Val Glu Ile Lys             100                 105                 110  SEQ ID NO: 11 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1               5                   10                  15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr             20                  25                  30 Ala Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met         35                  40                  45 Gly Trp Ile Asn Ala Gly Asn Gly Asn Thr Lys Tyr Ser Gln Lys Phe     50                  55                  60 Gln Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr 65                  70                  75                  80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys                 85                  90                  95 Ala Arg Gly Gly Tyr Tyr Gly Ser Gly Ser Asn Tyr Trp Gly Gln Gly             100                 105                 110 Thr Leu Val Thr Val Ser Ser          115 

The invention claimed is:
 1. A method of treating Crohn's disease (CD)in a human patient in need thereof, wherein the method comprises:selecting a high-risk CD human patient, and administering to thehigh-risk CD human patient, a triple combination therapy comprising ahumanized anti-α4β7 antibody, adalimumab, and methotrexate, wherein thetriple combination therapy is administered to the high-risk CD humanpatient according to the following dosing regimen: a. an initial dose of300 mg of the humanized anti-α4β7 antibody as an intravenous infusion,followed by a second subsequent dose of 300 mg of the humanizedanti-α4β7 antibody as an intravenous infusion at about two weeks afterthe initial dose; followed by a third subsequent dose of 300 mg of thehumanized anti-α4β7 antibody as an intravenous infusion at about sixweeks after the initial dose; b. an initial dose of 160 mg of adalimumabas a subcutaneous injection, followed by a second subsequent dose of 80mg of adalimumab as a subcutaneous injection, followed by a thirdsubsequent dose of 40 mg of adalimumab at about four weeks after theinitial dose; and c. an initial dose of 15 mg of methotrexate orallywherein the dosing regimen results in endoscopic remission, furtherwherein the anti-α4β7 antibody comprises an antigen binding region ofnonhuman origin and at least a portion of an antibody of human origin,wherein the humanized antibody has binding specificity for the α4β7complex, wherein the antigen-binding region comprises the CDRs: Lightchain: CDR1 SEQ ID NO:7 CDR2 SEQ ID NO:8 and CDR3 SEQ ID NO:9; and Heavychain: CDR1 SEQ ID NO:4 CDR2 SEQ ID NO:5 and CDR3 SEQ ID NO:6.
 2. Themethod of claim 1, wherein the humanized anti-α4β7 antibody has a heavychain variable region sequence of amino acids 20 to 140 of SEQ ID NO:1and/or a light chain variable region sequence of amino acids 20 to 131of SEQ ID NO:2.
 3. The method of claim 1, wherein the humanizedanti-α4β7 antibody has a heavy chain comprising amino acids 20 to 470 ofSEQ ID NO:1 and a light chain comprising amino acids 20 to 238 of SEQ IDNO:2.
 4. The method of claim 1, wherein the anti-α4β7 antibody isvedolizumab.
 5. The method of claim 1, wherein the high-risk CD humanpatient additionally is administered a dose of corticosteroid.
 6. Themethod of claim 1, further comprising administration of a subsequentdose of 300 mg of the humanized anti-α4β7 antibody as an intravenousinfusion at about four weeks after the third subsequent dose or at abouteight weeks after the third subsequent dose.
 7. The method of claim 6,further comprising administration of a subsequent dose of 300 mg of thehumanized anti-α4β7 antibody as an intravenous infusion at about everyeight weeks thereafter.
 8. The method of claim 7, further comprisingadministration of a subsequent dose of 300 mg of the humanized anti-α4β7antibody as an intravenous infusion at about every four weeks after 26weeks of therapy if CD is exacerbated.
 9. The method of claim 1, furthercomprising administration of a subsequent dose of 108 mg of thehumanized anti-α4β7 antibody as a subcutaneous injection at about everytwo or four weeks after the third subsequent dose.
 10. A method oftreating Crohn's disease (CD) in a human patient in need thereof,comprising administering to the human patient a triple combinationtherapy comprising vedolizumab, adalimumab, and methotrexate accordingto a triple combination therapy, wherein the triple combination therapycomprises administering vedolizumab at a dose of 300 mg at weeks 0, 2,and 6, followed by administration every 8 weeks thereafter;subcutaneously administering a 160 mg dose of adalimumab at week 0, an80 mg dose of adalimumab at week 2, and a 40 mg dose of adalimumab atweek 4 and every two weeks thereafter; and administering methotrexate.11. The method of claim 10, wherein adalimumab is discontinued at week26.
 12. The method of claim 10, wherein the methotrexate is administeredorally.
 13. The method of claim 10, wherein the methotrexate isdiscontinued at week
 34. 14. The method of claim 10, wherein the patientis a high-risk Crohn's disease patient.
 15. A method of treating Crohn'sdisease in a human patient in need thereof, comprising administering tothe human patient a triple combination therapy comprising vedolizumab,infliximab, and methotrexate, wherein the triple combination therapycomprises administering vedolizumab at a dose of 300 mg at weeks 0, 2,and 6, followed by administration every 8 weeks thereafter;intravenously administering infliximab at a dose of 5 mg/kg at weeks 0,2 and 6, and then every 8 weeks thereafter; and administeringmethotrexate.
 16. The method of claim 15, wherein infliximab isdiscontinued at week
 26. 17. The method of claim 15, wherein themethotrexate is administered orally.
 18. The method of claim 15, whereinthe methotrexate is discontinued at week 34.